Human behavior involves the unique capacities to regulate our own psychological states to pursue desired goals, bring our behavior in line with internal/external standards, manage our emotions, and cope with challenges and opportunities that arise. The term self-regulation denotes the processes through which people intentionally or automatically initiate, maintain, and terminate their own thoughts and behaviors in the service of pursuing personal goals. The importance of understanding self-regulation becomes obvious when one considers the array of public health problems that can be traced to problematic goal pursuit. Many behaviors that put people at increased risk for illness, disability, and death - such as obesity, eating disorders, smoking, alcohol abuse, suicidality, and drug addiction - involve difficulties with self-regulation. Thus, maladaptive self-regulation is an important contributory factor in a large number of psychological, social, and health-related problems. We believe that significant progress can be made in understanding and overcoming self- regulatory problems by combining existing theory and research in behavioral science with parallel findings in related disciplines. Recent developments in cognitive neuroscience (specifically, the role of the orbitofrontal cortex in self-regulation of goal pursuit) and imaging genetics (specifically, how heritable variability in the gene encoding catechol-O- methyltransferase [COMT], an enzyme that controls extracellular dopamine in the frontal cortex, influences processing of motivationally salient stimuli) offer synergistic perspectives on how failure in self-regulation could, for a particular subset of individuals, lead to chronically maladaptive behavior and increase vulnerability to a range of significant health problems. The aims of this R01 application are: (1) to validate a hypothesized gene/environment/self-regulation risk phenotype conferring vulnerability to failures of self- regulation, and (2) to test a novel set of cognitive/behavioral techniques that we predict will acutely reverse the dysfunctions that underlie self-regulatory failure. The proposed research will be conducted in two samples: adolescents, who are vulnerable to initiation of a number of health-risking behaviors and psychological problems, and college students, some of whom already engage regularly in such behaviors and manifest psychological difficulties. We predict that a combination of three contributory factors - individual differences in regulatory focus, COMT genotype, and chronic failure to attain a particular kind of personal goal - creates a self- regulation pathway to disordered behaviors with significant public health implications. PUBLIC HEALTH RELEVANCE: The aims of this R01 application are: (1) to conduct a program of translational research validating a hypothesized gene/environment/self-regulation risk phenotype conferring vulnerability to failures of self-regulation, and (2) to test a novel set of cognitive/behavioral techniques that we predict will acutely reverse the dysfunctions that underlie self-regulatory failure. We predict that we will observe, in both adolescent and college student samples, that a combination of three contributory factors - individual differences in regulatory focus, COMT genotype, and chronic failure to attain a particular kind of personal goal - creates a self- regulation pathway to a broad array of disordered behaviors and psychological states with significant public health implications, including tobacco use, alcoholism, mood disorders, obesity, eating disorders, and impulsivity. Based on this model, we anticipate that the theory- based brief change techniques will prove efficacious and will ultimately provide a basis for effective broader-scale therapeutic and preventive interventions in future studies.